INTRODUCTION: Recent biopsychological research on stress-related psychopathology shows promising evidence for the 5-hydroxytryptamine (5-HT) transporter linked polymorphic region (5-HTTLPR) genotype by life event interaction on depression. Yet, there appears to be variability in replicating such findings. From leading cognitive models of depression, it can be deduced that mainly high-impact events, particularly in stress-vulnerable, high trait neuroticism individuals who possess low coping abilities, can cause depression. OBJECTIVE: The current study therefore examines the interaction between the 5-HTTLPR genotype, impact of life events, and trait neuroticism on depression symptoms. PARTICIPANTS AND METHODS: A group of 771 healthy individuals, 595 women and 176 men aged 21.0+/-2.1 years, were genotyped for the 5-HTTLPR polymorphism and were rated for depressive symptoms, impact of life events, and neuroticism. RESULTS: Only the low-allele expressing (S) 5-HTTLPR carriers showed vulnerability to depression exclusively when they also reported exposure to high-impact events and showed high neuroticism. CONCLUSION: This suggests that cognitive vulnerabilities may mediate the 5-HTTLPR genotype by life event interaction on depression.